JPH0449548B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical Field] The present invention relates to novel tetrazole derivatives, pharmacologically acceptable salts thereof, and methods for producing them. [Prior art] British Patent No. 1381860 has anti-inflammatory properties.
-(P-chlorophenyl)-4-(tetrazole-
5-ylmethyl)thiazole, 2-cyclohexyl-4-tetrazol-5-ylmethyl)thiazole and 2-phenyl-4-(tetrazol-5
Tetrazole derivatives such as -yl)oxazole have been disclosed. [Object of the present invention] An object of the present invention is to provide a novel tetrazole derivative having an antilipemic effect, and another object is to provide a method for producing the novel tetrazole derivative. [Structure and effects of the present invention] The compound of the present invention has the general formula (However, R ¹ is a furyl group, a thienyl group, a phenyl group, an alkyl group, or a cycloalkyl group, Y is a sulfur atom or an oxygen atom, and X is a halogen atom.) It's salt. Examples of the compound [ ] of the present invention include, in the general formula [ ], R ¹ is an alkyl group such as a furyl group, a thienyl group, a phenyl group, a propyl group, a heptyl group, an undecyl group, or a cycloalkyl group such as a cyclohexyl group; , Y is a sulfur atom or an oxygen atom, and X is a chlorine atom, a fluorine atom, or a bromine atom. Among these, preferred compounds include, for example, in the general formula [], R ¹ is a furyl group, isopropyl group, heptyl group, undecyl group, or cyclohexyl group, Y is a sulfur atom or an oxygen atom, and X is a chlorine atom or a fluorine atom. Examples include compounds. Particularly preferable compounds include, for example, in the general formula []
Examples include compounds in which R ¹ is an isopropyl group, heptyl group, or cyclohexyl group, M is a sulfur atom, and X is a chlorine atom. According to the present invention, the compound [] has the general formula (However, R ¹ , Y and X have the same meanings as above.) It can be produced by reacting an azole compound represented by the following with ammonium azide (NH ₄ N ₃ ). The reaction between compound [] and ammonium azide can be easily carried out in an inert medium. Ammonium azide used in this reaction is used in addition to itself, hydrogen azide or hydrazoic acid and ammonia, or alkali metal azide or alkaline earth metal azide (e.g. sodium azide,
Potassium azide, magnesium azide, etc.) and ammonium salts (for example, ammonium chloride, ammonium sulfate) can be reacted to generate ammonium azide while being subjected to the reaction. Examples of inert solvents that can be used include dimethylformamide, dioxane, xylene, and toluene. This reaction is preferably carried out at about 100-150°C. When the compound of the present invention [] is used as a medicine,
It can be used in the free base form as well as its pharmaceutically acceptable salts. Examples of pharmacologically acceptable salts include alkali metal salts such as potassium salts and sodium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. It can be easily produced by a conventional method such as reaction with an alkali metal or alkaline earth metal hydroxide or oxide. When the compound of the present invention [ ] is used as a medicine, it can be administered either orally or parenterally. When the compound of the present invention [ ] is administered orally, it can be administered in the form of tablets, powders, capsules, granules, etc., which may be prepared using conventional excipients such as calcium carbonate, calcium phosphate, corn starch, and potato. It may contain starch, sugar, lactose, talc, magnesium stearate, etc. It may also be used as a liquid preparation such as an aqueous or oily suspension, liquid, syrup, or elixir. Furthermore, when administering parenterally, it is given in the form of an injection preparation, suppository, etc., and when it is an injection preparation, it is given in the form of a solution or suspension. For example, peanut oil, corn oil) or a non-aqueous solvent (for example, polyethylene glycol, polypropylene glycol, lanolin, coconut oil, etc.) may be contained. The essence may also be sterilized and/or contain adjuvants such as preservatives and stabilizers. The pharmaceutical dosage of the compound [] varies depending on the administration method, patient's age, weight, condition, and disease to be treated, but the preferred daily dosage is usually about 1 to about 20 mg/day for oral administration. Kg, especially about 5 to about 15 mg/Kg. The raw material compound [] of the present invention is a new compound and can be produced, for example, by the method shown in the following reaction formula. (However, in the above formula, R ₂ represents an ester residue,
(R ¹ and Y have the same meanings as above) That is, 3-cylamino-4-oxobutyric acid ester [] and a sulfurized condensing agent [e.g. 2,4-bis(methylthio)-2,4-dithiocyclodi-λ-phosphatine] in an inert solvent (tetrahydrofuran, dioxane, chloroform, etc.) at 0 to 150℃
React with to form a compound [ ] (Y = sulfur atom)
Alternatively, the compound [] and a dehydrating agent (e.g. phosphorus oxychloride) are mixed in an inert medium (chloroform,
dimethylformamide, dioxane, etc.], 0~
React at 110℃ to form compound [] (Y=oxygen atom)
The thus obtained compound [] and ammonia are mixed in an inert solvent (methanol, ethanol, etc.)
After reacting at 0 to 100°C to obtain an azole acetate amide derivative [], the compound was further dissolved in an inert solvent (chloroform, dimethylformamide,
It can be produced by reacting it with a dehydrating agent (thionyl chloride, phosphorus oxychloride, Vilsmeier-Heack reagent, etc.) in tetrahydrofuran, etc.). Experimental example (lipid lowering effect) The sample was mixed with powdered rat feed (sample content:
50mg%), and the mixture was administered to SD male rats (body weight:
The animals (120 to 140 g, 5 animals per group) were given free ingestion for one week, and then blood was collected from the tail under ether anesthesia. Using the collected blood, the serum cholesterol level and serum triglyceride level were measured by an enzymatic method. From these results, serum cholesterol and triglyceride reduction rates were determined using the following formula. The results of the serum lipid lowering effect are shown in Table 1 below. Reduction rate = [1-cholesterol value or triglyceride value of sample administration group/cholesterol value or triglyceride value of control group] x 100

[Table] Example 1 2-(4-chlorophenyl)-5-(2-furyl)
- Suspend 1.30 g of 4-cyanomethylthiazole, 1.5 g of sodium azide, and 1.5 g of ammonium chloride in 20 ml of dimethylformamide, and hold the mixture at 100-110℃.
Heat and stir for 10 hours. Dimethylformamide is distilled off under reduced pressure, and ethyl acetate and 10% hydrochloric acid are added to the residue to separate the layers. Separate the organic solvent layer and wash with water.
dry. The solvent is concentrated under reduced pressure, and the residue is crystallized with methanol to obtain 0.86 g of 5-{[2-(4-chlorophenyl)-5-(2-furyl)-4-thiazolyl]methyl}tetrazole. yield
58% mp220-222℃ (decomposition) IR (cm ^-1 ) υ ^Nujol _nax : 3150, 3130, 1575 MS (M/e): 343 (M ⁺ ), 40 (100) NMR (DMSO−d ₆ ) δ: 4.69 (2H, S), 6.73
(1H, dd, J = 4and2Hz), 6.96 (1H, d, J
= 4Hz), 7.59 and 7.95 (2H each, A ₂ ′B ₂ ′, J
= 9 Hz), 7.89 (1H, d, J = 2 Hz) Example 2 A reaction was carried out in the same manner as in Example 1 using 1.3 g of 2-(4-chlorophenyl)-5-(3-thienyl)-4-cyanomethylthiazole. By processing 5-
{[2-(4-chlorophenyl)-5-(3-thienyl)-4-thiazolyl]methyl}tetrazole
Obtain 1.38g. Yield 94% mp221-222℃ (decomposition) IR (cm ^-1 ) υ ^Nujol _nax : 3200, 1540 MS (M/e): 359 (M ⁺ ), 109 (100) NMR (DMSO−d ₆ ) δ: 4.58 (2H, S), 7.46
(1H, dd, J=5 and 1.5Hz), 7.61 and
7.96 (each 2H, A ₂ ′B ₂ ′, J=9Hz), 7.7~8.0
(2H, m) Example 3 2-(4-chlorophenyl)-5-phenyl-4
5-{[2
1.75 g of -(4-chlorophenyl)-5-phenyl-4-thiazolyl]methyl}tetrazole are obtained.
Yield 66% mp213~214℃ IR (cm ^-1 ) υ ^Nujol _nax : 2300~3000 (multiple absorption),
1570, 1555 MS (M/e): 353 (M ⁺ ), 147 (100) NMR (DMSO-d ₆ ) δ: 4.50 (2H, S), 7.4
~7.8 (7H, m), 7.96 (2H, A ₂ ′B ₂ ′, J=9
Hz) Example 4 2.0 g of 2-(4-chlorophenyl)-5-isopropyl-4-cyanomethylthiazole was reacted and treated in the same manner as in Example 1 above to obtain 5-{[2
-(4-chlorophenyl)-5-isopropyl-4
1.64 g of -thiazolyl]methyl}tetrazole are obtained. Yield 71% mp168-169℃ IR (cm ^-1 ) υ ^Nujol _nax : 3130, 3050, 1550, 1500 MS (M/e): 319 (M ⁺ ), 276 (M-iPr) NMR (DMSO-d ₆ ) δ: 1.32 (6H, d, J=
7Hz), 3.48 (1H, septet J = 7Hz), 4.48
(2H, S), 7.55 and 7.92 (each 2HA ₂ ′B ₂ ′, J
= 9 Hz) = 9 Hz), Example 5 5-
{[2-(4-chlorophenyl)-5-n-heptyl-4-thiazolyl]methyl}tetrazole 0.81g
get. Yield 72% mp122-124℃ IR (cm ^-1 ) υ ^Nujol _nax : 3110, 3020, 1550 MS (M/e): 375 (M ⁺ ), 262 (100) NMR (CDCl ₃ ) δ: 0.7-1.2 (3H, m), 1.2~
2.0 (10H, m), 2.95 (2H, t, J=7Hz),
4.44 (2H, S), 7.39 and 7.78 (2H each,
_{A2'B2 '} , J=9Hz) Example 6 5- {[2
-(4-fluorophenyl)-5-n-undecyl-4-thiazolyl]methyl}tetrazole 1.18 g
get. Yield 88% mp119-120℃ IR (cm ^-1 ) υ ^Nujol _nax : 3310, 1600, 1550 MS (M/e): 415 (M ⁺ ), 246 (100) NMR (CDCl ₃ ) δ: 0.7-1.1 (3H, m), 1.1~
2.0 (18H, m), 2.81 (2H, t, J=7Hz),
4.40 (2H, S), 6.9~7.3 and 7.6~7.85 (each
2H, m) Example 7 5-{[2
-(4-chlorophenyl)-5-cyclohexyl-
0.85 g of 4-thiazolyl]methyl}tetrazole is obtained. Yield 94% mp197~201℃ IRυ ^Nujol _nax (cm ^-1 ): 3120, 1550, 1500 MS (M/e): 359 (M ⁺ ), 288 (100) NMR (DMSO−d ₆ ) δ: 1.0~ 2.1 (10H, m),
2.7-3.3 (1H, m), 4.45 (2H, S), 7.53 and 7.88 (each 2H, A ₂ ′B ₂ ′, 9Hz) Example 8 2-(4-chlorophenyl)-5-(2-furyl)
5-{[2-
(4-chlorophenyl)-5-(2-furyl)-4-
1.80 g of oxazolyl]methyl}tetrazole is obtained. Yield 92% mp207~208℃ IRυ ^Nujol _nax (cm ^-1 ): 3140, 3050, 1550 MS (M/e): 327 (M ⁺ ), 28 (100) NMR (DMSO−d ₆ ) δ: 4.56 ( 2H, S), 6.58
(1H, dd, J=4 and 2Hz), 6.80 (1H,
d, J = 4Hz), 7.47 and 8.03 (2H each,
A ₂ ′B ₂ ′, J=9Hz), 7.59(1H, d, J=2
Hz) Example 9 0.80 g of 2-(4-chlorophenyl)-5-n-undecyl-4-cyanomethyloxazole was treated in the same manner as in Example 1 to obtain 5-{[2-
(4-fluorophenyl)-5-n-untesyl-
4-oxazolyl]methyl}tetrazole 0.57g
get. Yield 64% mp91-93℃ IRυ ^Nujol _nax (cm ^-1 ): 3120, 1610, 1556, 1490 MS (M/e): 399 (M ⁺ ), 230 NMR (CDCl ₃ ) δ: 0.8-1.1 (3H , m), 1.1~
2.0 (18H, m), 2.73 (2H, t, J = 7Hz)
4.24 (2H, S), 6.9~7.3 and 7.7~8.0 (each
2H, m) Reference Example 1 1) Add 2,4-bis(methylthio)-2,4 to a solution of 3.5 g of 4-(2-furyl)-3-(4-chlorobenzamide)-4-butyric acid ethyl ester in 100 ml of tetrahydrofuran. -dithiocyclo-di-λ
-Add 5.6 g of phosphatian at room temperature and stir. After further stirring at 40°C for 1 hour, the reaction solution was diluted with ethyl acetate and washed successively with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide solution, and saturated brine. Then, by concentrating and adding a small amount of ethanol to the residue and collecting by filtration, 2-[2
-(4-chlorophenyl)-5-(2-furyl)-
3.15 g of 1-thiazolyl]acetic acid ethyl ester are obtained. Yield 91% mp94-96℃ IRυ ^Nujol _nax (cm ^-1 ): 1720 MS (M/e): 347 (M ⁺ ) NMR (CDCl ₃ ): 1.26 (3H, t, J = 7Hz),
4.04 (2H, S), 4.22 (2H, q, J=7Hz),
6.49 (1H, dd, J=2 and 4Hz), 6.59
(1H, d, J = 4Hz), 7.39 and 7.87 ((each
2H, A ₂ ′B ₂ ′, J = 9Hz), 7.48 (1H, d, J
= 2 Hz) Thereafter, the compounds shown in Table 2 below are obtained by treating the corresponding raw material compounds in the same manner as above.

【table】

[Table] Reference Example 2 Dissolve 2.0 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-thiazolyl]acetic acid ethyl ester obtained in Reference Example 1 in 50 ml of methanol and add ammonium at 0°C. saturate and leave at room temperature for 3 days. Then, the solvent was distilled off, methanol was added to the residue, and the residue was collected by filtration to obtain 1.70 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-thiazolyl]acetic acid amide. Yield 93% mp220-221℃ (decomposition) IRυ ^Nujol _nax (cm ^-1 ): 3420, 3310, 3200, 1630 By treating the compounds in Table 2 of Reference Example 1 in the same manner as above, the compounds shown in Table 3 below were obtained. The compound shown is obtained.

【table】

[Table] Reference Example 3 Suspend 3.19 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-thiazolyl]acetamide obtained in Reference Example 2 in 10 ml of chloroform, and add 2 ml of phosphorus oxychloride. and 1 drop of pyridine and heated under reflux for 8 hours. The reaction solution is poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic solvent layer is separated, dried, and concentrated. The residue was purified with a silica gel column (developing solvent: chloroform) to obtain 2.50 g of 2-(4-chlorophenyl)-5-(2-furyl)-4-cyanomethylthiazole. Yield 83% mp132-133℃ IRυ ^Nujol _nax (cm ^-1 ): 2250, 1090, 830, 745 MS (m/e): 300 (M ⁺ , 100) NMR (CDCl ₃ ) δ: 4.12 (2H, S ), 6.5~6.8
(2H, m), 7.43 and 7.89 (each 2H, A ₂ ′B ₂ ′,
J=9Hz), 7.58 (1H, d, J=2Hz) The compounds listed in Reference Example 2 and Table 3 were treated in the same manner as in Reference Example 3 to obtain the compounds shown in Table 4 below.

【table】

Claims (1)

[Claims] 1. General formula (However, R ¹ is a furyl group, thienyl group, phenyl group, alkyl group or cycloalkyl group, Y is a sulfur atom or an oxygen atom, and X is a halogen atom) or a pharmacologically acceptable tetrazole derivative thereof salt. 2 General formula (wherein R ¹ is a furyl group, thienyl group, phenyl group, alkyl group or cycloalkyl group, Y is a sulfur atom or an oxygen atom, and X is a halogen atom) is reacted with ammonium azide, A general formula characterized in that, if necessary, the resulting compound is converted into a pharmacologically acceptable salt. (However, R ¹ , Y and X have the same meanings as above.) A method for producing a tetrazole derivative or a pharmacologically acceptable salt thereof.